Research and Development Department, Wuhan YZY Biopharma Co., Ltd, Wuhan, China.
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Front Immunol. 2021 May 10;12:654080. doi: 10.3389/fimmu.2021.654080. eCollection 2021.
Vγ2Vδ2 T cell-based immunotherapy has benefited some patients in clinical trials, but the overall efficacy is low for solid tumor patients. In this study, a bispecific antibody against both PD-L1 and CD3 (PD-L1 x CD3), Y111, could efficiently bridge T cells and PD-L1 expressing tumor cells. The Y111 prompted fresh CD8+ T cell-mediated lysis of H358 cells, but spared this effect on the fresh Vδ2+ T cells enriched from the same donors, which suggested that Y111 could bypass the anti-tumor capacity of the fresh Vγ2Vδ2 T cells. As the adoptive transfer of the expanded Vγ2Vδ2 T cells was approved to be safe and well-tolerated in clinical trials, we hypothesized that the combination of the expanded Vγ2Vδ2 T cells with the Y111 would provide an alternative approach of immunotherapy. Y111 induced the activation of the expanded Vγ2Vδ2 T cells in a dose-dependent fashion in the presence of PD-L1 positive tumor cells. Moreover, Y111 increased the cytotoxicity of the expanded Vγ2Vδ2 T cells against various NSCLC-derived tumor cell lines with the releases of granzyme B, IFNγ, and TNFα . Meanwhile, the adoptive transferred Vγ2Vδ2 T cells together with the Y111 inhibited the growth of the established xenografts in NPG mice. Taken together, our data suggested a clinical potential for the adoptive transferring the Vγ2Vδ2 T cells with the Y111 to treat PD-L1 positive solid tumors.
基于 Vγ2Vδ2 T 细胞的免疫疗法已使一些临床试验中的患者受益，但对实体瘤患者的总体疗效较低。在这项研究中，一种针对 PD-L1 和 CD3 的双特异性抗体（PD-L1 x CD3），Y111，能够有效地将 T 细胞和 PD-L1 表达的肿瘤细胞桥接起来。Y111 促使新鲜的 CD8+ T 细胞介导对 H358 细胞的裂解，但对从同一供体中富集的新鲜 Vδ2+ T 细胞没有这种作用，这表明 Y111 可以绕过新鲜 Vγ2Vδ2 T 细胞的抗肿瘤能力。由于扩展的 Vγ2Vδ2 T 细胞的过继转移在临床试验中被批准是安全且耐受良好的，我们假设扩展的 Vγ2Vδ2 T 细胞与 Y111 的组合将提供一种替代的免疫疗法方法。在 PD-L1 阳性肿瘤细胞存在的情况下，Y111 以剂量依赖的方式诱导扩展的 Vγ2Vδ2 T 细胞的激活。此外，Y111 增加了扩展的 Vγ2Vδ2 T 细胞对各种 NSCLC 衍生的肿瘤细胞系的细胞毒性，伴随着颗粒酶 B、IFNγ 和 TNFα 的释放。同时，过继转移的 Vγ2Vδ2 T 细胞与 Y111 一起抑制了 NPG 小鼠中已建立的异种移植物的生长。总之，我们的数据表明，用 Y111 过继转移 Vγ2Vδ2 T 细胞来治疗 PD-L1 阳性实体瘤具有临床潜力。
